The preparation of doxycycline and other alpha-6-deoxytetracyclines was first described in Blackwood et al. U.S. Pat. No. 3,200,149 granted Aug. 10, 1965. That patent described their preparation by the catalytic hydrogenation of a corresponding 6-methylene intermediate, e.g., in the case of doxycycline, 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline (11a-chloro methacycline) or 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline (methacycline), in the presence of a heterogeneous noble metal catalyst, e.g. palladium on carbon. The Blackwood patent disclosed the production, in yields of up to about 50%, of equimolar proportions of the diastereoisomers (epimers) of the 6-deoxytetracyclines. In the case of doxycycline, the patent disclosed the co-production of the corresponding beta epimer, beta-6-deoxy-5-oxytetracycline.
Subsequent efforts have been directed to the development of syntheses for producing the 6-deoxytetracyclines in greater yields and with greater stereoselectivity of formation of the desired alpha epimers, e.g., doxycycline. Thus, Korst U.S. Pat. No. 3,444,198 granted May 13, 1969, disclosed that the stereoselectivity of formation of the alpha epimers may be increased when the noble metal hydrogenation catalyst is poisoned. The Korst patent described the formation of epimeric mixtures of the 6-deoxytetracyclines in total yields of up to about 60%, with the stereoselective production of the alpha epimers in amounts of up to about 90% of the epimeric product mixtures.
The use of rhodium chloride/triphenylphosphine and similar complexes as homogeneous, stereospecific hydrogenation catalysts in the production of doxycycline and other alpha-6-deoxy-5-oxytetracyclines has also been extensively discussed in the patent literature. See, for example, U.S. Pat. Nos. 3,907,890; 3,962,331; 4,001,321; 4,207,258; 4,550,096; 4,743,699; and French Patent No. 2,216,268.
Other noble metal or noble metal salt heterogeneous hydrogenation catalysts for 6-methylenetetracyclines have also been disclosed in the literature. For example, Faubl et al. in U.S. Pat. No. 3,962,131 describes a heterogeneous catalyst for use in hydrogenating methacycline. The Faubl catalyst is produced by reacting rhodium trichloride and sodium acetate in methanol at temperatures in excess of 50.degree. C., and reacting this system with triphenylphosphine. The Faubl catalyst is reported to exhibit stereoselectivity for the alpha epimers by a factor of at least 9:1 versus the beta epimer with a yield of 98.8% reported in the sole Faubl example.
Catalytic hydrogenation of methacycline using a catalytic amount of rhodium metal together with a phosphine, preferably triphenylphosphine, and a promoter, e.g., excess acid (over that required to form an acid addition salt with methacycline), is disclosed by Morris, Jr. in U.S. Pat. No. 3,954,862. The heterogeneous rhodium metal catalyst may be of the non-supported or supported type, e.g., supported by carbon, silica, alumina or barium sulfate.
Another process for the heterogeneous hydrogenation of methacycline is disclosed by Page in U.S. Pat. No. 4,597,904. Page employs a rhodium salt catalyst wherein the rhodium is bonded to a polysiloxane carrier, generally an aminopolysiloxane. The methacycline hydrogenation is accomplished in the presence of a tertiary phosphine, e.g., triphenylphosphine. The Page hydrogenation process is reported to be sterospecific, typically yielding less than 0.2% beta epimer. However, polysiloxane materials are known to be sensitive to elevated temperatures, e.g., greater than 90.degree. C., and any breakdown of the polysiloxane carrier would adversely impact the functionality and the recylability of the Page rhodium salt catalyst.
The present invention is directed to an improved process for the production of doxycycline and other alpha-6-deoxytetracyclines, wherein the desired alpha epimer is produced in both high yield and stereospecificity, and the noble metal constituent of the hydrogenation catalyst may be utilized in smaller proportions than heretofore required and is readily recoverable from the reaction mixture for reuse. Other objects and advantages of this invention will be apparent from the following description of preferred embodiments thereof.